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Effects of immunogenic cell death-inducing chemotherapeutics on the immune cell activation and tertiary lymphoid structure formation in melanoma.
- Source :
-
Frontiers in immunology [Front Immunol] 2024 Feb 07; Vol. 15, pp. 1302751. Date of Electronic Publication: 2024 Feb 07 (Print Publication: 2024). - Publication Year :
- 2024
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Abstract
- Background: The infiltration and activation of immune cells in the tumor microenvironment (TIME) affect the prognosis of patients with cancer. Tertiary lymphoid structure (TLS) formation favors tumour- infiltrating-lymphocyte (TIL) recruitment and is regarded as an important indicator of good prognosis associated with immunotherapy in patients with tumors. Chemotherapy is currently one of the most commonly used clinical treatment methods. However, there have been no clear report to explore the effects of different types of chemotherapy on TLS formation in the TIME. This study examined the effects of immunogenic cell death (ICD)-inducing chemotherapeutics on immune cells, high-endothelial venules (HEV), and TLSs in mouse melanomas.<br />Methods: Doxorubicin (an ICD inducer), gemcitabine (non-ICD inducer), and a combination of the two drugs was delivered intra-peritoneally to B16F1-loaded C57BL/6 mice. The infiltration of immune cells into tumor tissues was evaluated using flow cytometry. HEV and TLS formation was assessed using immunohistochemistry and multiple fluorescent immunohistochemical staining.<br />Results: Doxorubicin alone, gemcitabine alone, and the two-drug combination all slowed tumor growth, with the combined treatment demonstrating a more pronounced effect. Compared with the control group, the doxorubicin group showed a higher infiltration of CD8 <superscript>+</superscript> T cells and tissue-resident memory T cells (T <subscript>RM</subscript> ) and an increase in the secretion of interferon-γ, granzyme B, and perforin in CD8 <superscript>+</superscript> T subsets and activation of B cells and dendritic cells. Doxorubicin alone and in combination with gemcitabine decreased regulatory T cells in the TIME. Moreover, doxorubicin treatment promoted the formation of HEV and TLS. Doxorubicin treatment also upregulated the expression of programmed cell death protein (PD)-1 in CD8 <superscript>+</superscript> T cells and programmed cell death protein ligand (PD-L)1 in tumor cells.<br />Conclusions: These results indicate that doxorubicin with an ICD reaction promotes TLS formation and increases PD-1/PD-L1 expression in tumor tissues. The results demonstrate the development of a therapeutic avenue using combined immune checkpoint therapy.<br />Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.<br /> (Copyright © 2024 Zhao, Zhao, Zhang, Wang, Yu, Dong, Yang, Zhang, Sun, Hao and Ren.)
- Subjects :
- Humans
Animals
Mice
CD8-Positive T-Lymphocytes
Gemcitabine
Immunogenic Cell Death
Mice, Inbred C57BL
Doxorubicin pharmacology
Doxorubicin therapeutic use
Doxorubicin metabolism
Deoxycytidine
Apoptosis Regulatory Proteins metabolism
Tumor Microenvironment
Melanoma drug therapy
Melanoma metabolism
Tertiary Lymphoid Structures pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1664-3224
- Volume :
- 15
- Database :
- MEDLINE
- Journal :
- Frontiers in immunology
- Publication Type :
- Academic Journal
- Accession number :
- 38384466
- Full Text :
- https://doi.org/10.3389/fimmu.2024.1302751